Advanced manufacturing: FDA official sees room for growth

The US Food and Drug Administration (FDA) is investing in research to spur the uptake of advanced manufacturing, yet this research has not yet translated into full-scale adoption of these technologies.

While over 10% of its drug center’s research budget targets advanced manufacturing, less than one percent of applications utilize this method of manufacturing, said Adam Fisher, director of the science staff for the Office of Pharmaceutical Quality at the Center for Drug Evaluation and Research (CDER), who spoke at an 18 July meeting cosponsored by the United States Pharmacopoeia (USP) and the Regulatory Affairs Professionals Society (RAPS).
 
At the meeting, Fisher provided an update of the regulatory landscape for advanced manufacturing technologies. According to the numbers presented at the meeting, uptake to advanced manufacturing continues to be slow. To date, Fisher said that FDA has approved 20 applications using advanced manufacturing methods. This is a small increase over the 16 applications approved as of last October 2022. (RELATED: Advanced manufacturing: GAO, USP reports say regulatory enhancements needed, Regulatory Focus 14 March 2023)
 
Advanced manufacturing can include novel manufacturing methods to improve process robustness, novel dosage forms, continuous manufacturing, new modeling tools for analytical testing and novel container closure systems.
 
Fisher also sought to dispel some common myths that may be impeding the more widespread adoption of advanced manufacturing technologies.
 
Multiple benefits of continuous manufacturing
 
At the meeting, Fisher exhorted the benefits of continuous manufacturing, asserting that continuous manufacturing applicants had shorter times to approval and marketing compared to batch applications, translating into between $100 to $500 million in early revenue, and that there are no substantial regulatory barriers for continuous manufacturing related to manufacturing process changes and pre-approval inspections.
 
These findings were published in an article co-written by Fisher and other FDA colleagues in surveying six solid oral drug products with approved applications and used CM, comparing them to 134 approved new drug applications (NDA) for batch processes. (RELATED: Continuous manufacturing applicants saw quicker approvals, higher revenue than batch applicants, Regulatory Focus 6 July 2022)
 
 
Fisher gave an example of a case study showing that one company that switched to continuous from batch processing reported a 50% reduction in operating costs, a 33% reduction in waste, an 80% reduction in manufacturing and testing time, and a 66% reduction in product testing to release.
 
Another advantage of adopting continuous manufacturing is the ability to reduce drug shortages though adoption of more agile manufacturing techniques. FDA conducted a survey of health care providers which found that over 80% of physicians, including cardiologists and dermatologists, reported that their patients have had trouble filling a prescription due to drug shortages. Fisher said that these shortages were an issue before COVID-19.
 
FDA has long encouraged the adoption of advanced manufacturing; the agency claims that advanced manufacturing methods can help companies reduce costs and quality defects and can improve global competitiveness of US manufacturing. (RELATED: FDA officials tout progress and achievements in advanced manufacturing, Regulatory Focus 15 October 2021)
 
 
FDA investing in advanced manufacturing research
 
Fisher said CDER’s science and research program has heavily invested in research to spur the development of advanced technologies, including continuous manufacturers, and has funded 61 intramural and extramural research projects.
 
In the intramural space, these projects include funding for 10 advanced manufacturing projects, 16 projects for precision analytics, 11 projects for advanced manufacturing for biopharmaceuticals, three projects exploring manufacturing of glycoproteins, one project exploring manufacturing synthetic nucleic acid sequences, and four projects for process modeling, artificial intelligence and machine learning (AI/ML).
 
In the extramural area, the agency has funded collaborations through grants and contracts including three projects for “Industry 4.0” and smart manufacturing, six projects for novel manufacturing methods, four projects for novel process analytical technologies, two projects for process modeling and simulation and one product aimed at advanced manufacturing training.
 
The intention of these projects is to drive regulatory actions and to guide guidance and the development of new standards.
 
Common myths debunked
 
Fisher pointed out that some common myths may be impeding the adoption of these advanced manufacturing technologies. The first myth is that continuous manufacturing is mandated by FDA. This is not the case. He said that “FDA approves drugs if they comply with standards, regulations and laws.” He added that continuous manufacturing is not for every company.
 
Another myth is that continuous manufacturing is just for innovator companies. He said that this is also not the case and that “multiple developers of generics have engaged with CDER’s [Emerging Technologies Program] ETP.”
 
Yet another misconception is that it takes FDA longer to review and approve these applications, which is not the case. The last myth is that generic companies are required to implement continuous manufacturing if the innovator company does so, Fisher said.
 
Continuous manufacturing field is evolving
 
Fisher discussed how continuous manufacturing has evolved over the past eight years with the establishment of ETP in 2015 to work with manufacturers in developing these advanced technologies and then the approval of the first product made on a continuous manufacturing line, Vertex’s Orkambi (lumacaftor/ivacaftor) to treat cystic fibrosis.
 
The ETP has since accepted over 50 proposals for continuous manufacturing since the program’s inception. FDA has also approved 20 total submissions incorporating emerging technologies, not all of which were continuous manufacturing. Among these approvals are a drug product using continuous manufacturing for active pharmaceutical ingredient synthesis, a continuous biomanufacturing process, a drug product that can be made using a batch or continuous process and three drug products that can be made using the same continuous manufacturing line.
 
USP workshop
 

Editor's note: this article was updated on 20 July 2023 to clarify the sponsorship of this workshop.